neuropsychiatric aspects of marijuana use mj and... · 2018-03-20 · insufficient evidence for...
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Neuropsychiatric Aspects
of Marijuana UseDIANA WERTZ, MD, PHD
3/23/18
Disclosures
My spouse is employed by Denali Therapeutics and he is a stockholder
Objectives
Participants will be able to:
Discuss the relative potency of different forms of marijuana
State ways in which risks are different for adolescent users vs adult users of
marijuana
Discuss the risks vs benefits of using different forms of marijuana and tailor
patient education based on the unique characteristics of the patient.
State the literature findings regarding IQ and psychosis for marijuana users
State several medical conditions where there is some evidence for the
beneficial effects of marijuana
When a patient says they smoke Marijuana what image comes to mind?
When a patient says they smoke Marijuana what image comes to mind?
Routes of Administration
Smoking (joint, blunt)
Immediate onset, lasts 1-3 hours
Vaporizing – heat to ~200 degrees C (below point of combustion)
Near immediate onset
Oral ingestion
Delay in onset 30 – 60 minutes, lasts up to 4 hours, variable 1st pass metabolism
“Blasting dabs”
Marijuana is complex from a
pharmacological point of view
“Cannabinoids” – General term for all compounds
from the cannabis plant
THC is the major psychoactive component
Cannabis/Hemp plant makes ~400 chemicals
~ 70 of these are true “cannabinoids” (structurally)
Some psychoactive and some not
Notable nonpsychoactive compounds include
cannabinol and cannabidiol
Hua, Vemuri, et. Al., (2016) Cell, Oct 2016
Different THC Concentration in Various
Parts of the Cannabis Plant
Potency in descending
order:
Flowers
Upper leaves
Lower leaves
Stems
Seeds
Different THC Concentration in Various
Parts of the Cannabis Plant
Percentage by weight of THC content:
0.5%-5% THC: MJ containing mostly leaves and stems
2%-8% THC: Hashish, dried cannabis resin and compressed flowers
7%-30% THC: Flowering tops of female plants (“sinsemilla”)
15%-80% THC: Hash Oil, organic solvent used to extract THC from Hashish or MJ
“Fiber type” cannabis, has low THC content <0.4% but higher cannabidiol content
Components of Cannabis
Delta-9-tetrahydrocannabinol = THC
Main component of cannabis responsible for the high of smoking cannabis
Associated with psychosis
Cannabidiol (CBD)
Does not produce a high
Anxiolytic, sedative, anticonvulsive, antiemetic, antipsychotic, anti-
inflammatory and antitumor effects
THC to CBD ratio
Generally a THC-to-CBD ratio of 1:1 is thought to be clinically preferable for
medical marijuana
Street Cannabis THC/CBD ratio:
1995 it was 14:1
2014 it was 80:1
FDA Approved Medications Derived
from Cannabis
US FDA Cannabis-derived compounds approved for nausea/emesis associated with
cancer chemotherapy and/or cachexia from wasting diseases:
Dronabinol (Marinol) – synthetic THC
Schedule III
Nabilone (Cesamet)
Schedule II
Syndros (liquid synthetic THC) – Schedule II
Dronabinol/THC Nabilone
FDA Approved Medications Derived
from Cannabis
US FDA Cannabis-derived compounds approved for nausea/emesis associated with
cancer chemotherapy and/or cachexia from wasting diseases:
Dronabinol (Marinol) – synthetic THC
Schedule III
Nabilone (Cesamet)
Schedule II
Syndros (liquid synthetic THC) – Schedule II
Nabiximols (Sativex) – THC/cannabadiol (1:1) spray (not approved in US yet) likely
will be approved for cancer pain and spasticity in multiple sclerosis.
Cannabidiol (Epidiolex) – Orphan drug status in US for the pediatric epilepsy
syndromes of Dravet and Lennox-Gastaut syndromes
Dronabinol/THC Nabilone
Plant Derived versus Endogenous Ligands
for Human Cannabis Receptors
Natural versus Synthetic Ligands for CBRs
Spice
K2
Kush
Potpourri
Skunk
Moon Rocks
Genie
Aroma
Krypton
Bonzai
Rapidly evolving other names
Natural versus Synthetic Ligands for CBRs
Spice
K2
Kush
Potpourri
Skunk
Moon Rocks
Genie
Aroma
Krypton
Bonzai
Rapidly evolving other names
“Probationer’s weed” (does not show on standard Utox)
Variety of chemical structures
UNTESTED FOR SAFETY IN HUMANS!!!!
4 General Structural Classes of Cannabinoids
In the late 2000s, two of Huffman's cannabinoid
compounds began being sold in Germany
as marijuana alternatives known as K2 and Spice.
"I figured once it got started in Germany it was going
to spread. I'm concerned that it could hurt people,"
Huffman said. "I think this was something that was
more or less inevitable. It bothers me that people are
so stupid as to use this stuff".
Natural versus Synthetic Ligands for CBRs
First introduced in 2004
Generally full agonists (vs THC partial
agonist)
Binding affinities 5-10,000 times higher
than THC at human CB-1/CB-2
receptors
Natural versus Synthetic Ligands for CBRs
First introduced in 2004
Generally full agonists (vs THC partial agonist)
Binding affinities 5-10,000 times higher than THC at human CB-1/CB-2 receptors
Users describe as “intense and trippy”, higher doses lead to hallucinations/paranoia
Herbs often used as carrier, “hot spots” can lead to huge batch to batch variations in potency.
More likely to cause psychosis and adverse effects
The Last Chemical Structure…I Promise
Clinical Uses of Medical Marijuana
Conditions with multiple positive RCTs for Medical Marijuana:
Chronic Pain
Multiple Sclerosis
Neuropathic Pain
Other conditions: epilepsy, ALS, Parkinson Disease, HIV/AIDS, Huntington Disease
FDA approved Cannabis derived medications:
Dronabinol (Marinol) & Nabilone(Cesamet) are useful for nausea and cachexia
In HIV + patients with cachexia, both smoked MJ and dronabinol (5mg) increased body weight in a dose dependent manner.
MJ caused intoxication
Dronabinol did not cause intoxication
https://medicalmarijuana.procon.org/view.resource.php?resourceID=000881http://www.governing.com/gov-data/state-marijuana-laws-map-medical-recreational.html
Clinical Aspects of Recommending Medical MJ
Marijuana remains a Schedule I drug
which has impeded research
American Academy of Pediatrics has
called for it to be rescheduled as a
Schedule II substance to facilitate
research
Little research into efficacy, dosage,
adverse effects and drug interactions
for medical marijuana
Clinical Aspects of Recommending Medical MJ
Marijuana remains a Schedule I drug which has impeded research
American Academy of Pediatrics has called for it to be rescheduled as a Schedule II substance to facilitate research
Little research into efficacy, dosage, adverse effects and drug interactions for medical marijuana
State laws generally suggest patients must have:
Debilitating condition
Multiple failed trials of FDA approved cannabinoids
Lack of substance use d/o, psychosis or unstable mood/anxiety d/o
Residence in a state where medical marijuana is legal
Warn re psychiatric risk, operating a vehicle
Clinical Aspects of Recommending Medical MJ
Clinicians may be hesitant to certify patients to receive medical MJ due to
concerns over variability in dosing once at the dispensary
Clinicians who were eligible to certify patients for access to marijuana were less
likely to recommend it than those who were not eligible to certify (85% vs 92%)
Clinicians cited lack of knowledge of state vs federal laws, lack of
education, and lack of evidence based research as the key barriers to
certifying patients to receive MJ
Rachel Peachman JAMA 2017, vol 319, #9, p. 852-853
Clinical Aspects of Recommending Medical MJ
“And with the current system, I have no control. I would certify it, and then my
patients would go to a [dispensary] that has nothing to do with me, yet
decides which brand to give, which strain to give, whether to go up or go
down in dosage.”
Stefan Friedrichsdorf, MD, medical director of the Department of Pain Medicine,
Palliative Care and Integrative Medicine at Children’s Minnesota
Rachel Peachman JAMA 2017, vol 319, #9, p. 852-853
Cannabinoid Dose and Label Accuracy in
Medical Cannabis Products
Studies suggest improved clinical benefit and fewer adverse effects with a THC: CBD ratio of 1:1.
Purchased 75 different products from dispensaries in Seattle, LA, SF sent them for chemical analysis
Accurately labeled was considered to be THC and CBD content within 10% of the labeled values, underlabeled if the content was more than 10% above the labeled values, and overlabeled if the content was more than 10% below the labeled values
Vandrey, R., Raber, J. C., et. al., JAMA (2015) vol 313, #24. p. 2491
Cannabinoid Dose and Label Accuracy in
Medical Cannabis Products
Studies suggest improved clinical benefit and fewer adverse effects with a THC: CBD ratio of 1:1.
Purchased 75 different products from dispensaries in Seattle, LA, SF sent them for chemical analysis
Accurately labeled was considered to be THC and CBD content within 10% of the labeled values, underlabeled if the content was more than 10% above the labeled values, and overlabeled if the content was more than 10% below the labeled values
With respect to THC content:
17% were accurately labeled
23% were underlabeled
60% were overlabeled
The median THC:CBD ratio of products with detectable CBD was 36:1, 7 had ratios of less than 10:1, and only 1 had a 1:1 ratio
Vandrey, R., Raber, J. C., et. al., JAMA (2015) vol 313, #24. p. 2491
Medical Marijuana for Neuropathic Pain
They looked at 16 studies with 1750
participants
Plant or synthetic THC, THC/CBD spray,
herbal cannabis
Primary Outcome: Cannabis-based
medicines may increase the number
of people with 50% or greater pain
relief c/t placebo. NNT 20
Secondary Outcome: 30% or greater
reduction in pain c/t placebo. NNT 11
Mucke, M, Philips, T., et. al., Cochrane Database of Systematic Reviews 2018, Issue 3. Art. No. CD012182.
Medical Marijuana for Neuropathic Pain
They looked at 16 studies with 1750
participants
Plant or synthetic THC, THC/CBD spray,
herbal cannabis
Primary Outcome: Cannabis-based
medicines may increase the number
of people with 50% or greater pain
relief c/t placebo. NNT 20
Secondary Outcome: 30% or greater
reduction in pain c/t placebo. NNT 11
Cannabis-based medicines may
increase nervous system adverse
events c/t placebo with NNH of 3
Psychiatric disorders occurred in 17%
of participants using cannabis-based
medicines and in 5% of those using
placebo with a NNH 8
Mucke, M, Philips, T., et. al., Cochrane Database of Systematic Reviews 2018, Issue 3. Art. No. CD012182.
Multiple Sclerosis
Clinicians might offer oral cannabis extract for spasticity symptoms and pain (excluding central neuropathic pain) (Level A)
The subjective benefit is possibly maintained for 1 year
Clinicians might offer Sativexoromucosal cannabinoid spray (nabiximols) for spasticity symptoms, pain, and urinary frequency (Level B)
No evidence for efficacy with tremor
“After cannabis treatment, the subjects consistently showed reduced cognitive performance (Paced Auditory Serial Addition Test)”
Patients with MS fared worse on measures of posture and balance 10 minutes after smoking 1 marijuana cigarette (but control patients did not experience these effects)
Yadav, V. et. al. (2014) Neurology, vol 82, p. 1083-1092.
Medical Marijuana and Epilepsy
Cannabidiol has moderate
anticonvulsive effects
Starting in the 1940s it was used for
children with treatment resistant
epilepsy
CB1 receptor plays a critical role in
neuronal firing, being studied for
treatment of epilepsy
American Academy of Neurology has
published a systematic review stating
the evidence for medical MJ (not
CBD) in controlling epilepsy is undetermined “data neither support
nor refute”
American Academy of Neurology
goes on to say weigh risks/benefits
carefully as the rate of serious
psychiatric side effects was 1%
Koppel, B. et, al. (2014) Neurology, vol 82, p. 1556-1563
CBD and Epilepsy
2018 Systematic Review of CBD (and
other MJ products) as an adjunctive
medication for treatment resistant
epilepsy
CBD doses were 2.5 - 20 mg/kg/day
Pharmaceutical grade CBD
Insufficient evidence for cannabis
sativa, CBD:THC combinations, or oral
cannabis extracts
Stockings, E., Zagic, D., et, al. (2018) J. Neurol Neurosurg Psych, vol 0, p. 1-13
CBD and Epilepsy
2018 Systematic Review of CBD (and other MJ products) as an adjunctive medication for treatment resistant epilepsy
CBD doses were 2.5 - 20 mg/kg/day
Pharmaceutical grade CBD
Insufficient evidence for cannabis sativa, CBD:THC combinations, or oral cannabis extracts
CBD was more likely to produce > 50% reduction in seizures c/t placebo (n = 291) with a NNT = 8
48% of patients achieved > 50% reduction in seizures
~ 5 % became seizure free
NNT for improved quality of life was 5
NNH 164 for pt to withdraw due to adverse effects
NNH 3 for any adverse side effect
Stockings, E., Zagic, D., et, al. (2018) J. Neurol Neurosurg Psych, vol 0, p. 1-13
Schizophrenia and Marijuana Use
Numerous large, prospective,
longitudinal studies suggest that use of
cannabis is associated with an
increase in risk for schizophrenia,
worsening symptoms, and is
associated with a poorer prognosis
(even after controlling for other
substance use)
THC can cause acute, transient and
dose-dependent psychosis
Volkow, N. D., Swanson, J. M., et. al. (2016) JAMA Psychiatry, Vol 73, #3, p292-297
Schizophrenia and Marijuana Use
Numerous large, prospective,
longitudinal studies suggest that use of
cannabis is associated with an
increase in risk for schizophrenia,
worsening symptoms, and is
associated with a poorer prognosis
(even after controlling for other
substance use)
THC can cause acute, transient and
dose-dependent psychosis
Risk factor but causality not
established:
use of cannabis increases the risk of
non–affective psychotic illness three- to
seven fold
High potency cannabis daily use
increases risk to 5-12 fold in various
studies
Volkow, N. D., Swanson, J. M., et. al. (2016) JAMA Psychiatry, Vol 73, #3, p292-297
Risk for Psychosis
Bechtold et. al. found that for each additional year
adolescent boys used cannabis, their frequency of
subclinical paranoia and hallucinations rose 133% and 92%
respectively.
Followed prospectively over about 20 years
Level of symptomatology persisted even after at least 1 yr of
abstinence
Bourque et. al. found the trajectory of increasing psychotic
experiences was associated with steeper growth of
cannabis use from age 13 to 16 (N = 2566)
Bechtold, J., Hipwell, A., et. al. (2016) AJP vol 173, #8, p. 781-789.
Bourque, Afzali, O’Leary-Barrett J. Child Psychology and Psychiatry July 2017
Synthetic Cannabinoids
Case reports of patient using spice who experience psychotic catatonia.
Some reports of temporary Parkinson-like symptoms
Synthetic Drug Abuse Prevention Act (2012), synthetic MJ products
Schedule 1
Review of 4000 cases (26 deaths) found most common side effects:
tachycardia (33-77%), agitation (16-41%) and nausea (13-94%). Most
people tolerate them fairly well actually.
Most individuals who use cannabis do not develop
schizophrenia…
The strongest risk factor for schizophrenia remains
having a close family member with schizophrenia
CBD as an adjunct for psychosis?
RDBPC parallel group study of CBD 1000 mg/day as an adjunctive
treatment for schizophrenia (N ~ 40 in each arm)
Patients receiving CBD had significantly (p = 0.02) lower levels of positive
psychotic symptoms but the effects were modest
CDB treatment led to very few adverse effects
Mechanism of attenuating psychosis unknown
Proposed that CBD inhibits the breakdown of anandamide, the endogenous
ligand for CB1
McGuire, P., Robson, P., et. al., (2018) AJP vol 175, #3, p 225-231.
Long-Term Cognitive Effects of
Marijuana Use
Although it is well established that acute use of cannabis impairs memory,
executive functioning and attention, studies show varying effects on long
term functioning (when not acutely intoxicated)
After chronic use, most users do just as well as controls on simple tests of
attention, memory, and executive functioning
MRI functional imaging studies suggest people are able to compensate
by recruiting other areas of the brain on simple and moderate complexity
tasks.
Impairment does seem to emerge in studies under complex and
demanding situations
Cohen, K. and Weinstein, A. (2018) Brain Sci., vol 8, p 40
Cognitive Effects of Marijuana Use
Exposure to cannabis during the
adolescent period may induce long
term cognitive impairments
All stages of memory, including
encoding, consolidation, and retrieval,
are altered.
Persistent users and dependent users
lost about six IQ points, while nonusers
gained about one IQ point (Meier et.
al. (2012) PNAS, 109 # 40 p. 2657)
Adolescent onset -8 IQ points
The longer that cannabis is used, the
more pronounced is the cognitive
impairment
At what age is it safe to begin using Cannabis?
Brain development is an ongoing
process thought to continue until age
25
Endocannabinoid system is involved in
brain development
Axon elongation
Synaptic pruning
Neuronal migration
Neuronal differentiation/maturation
Unlike endogenous ligands for the
cannabinoid receptors which are
short acting, cannabis activates
receptors in a prolonged
nonphysiological manner
De’Souza, D. C., Ranganathan, M. (2015) Vol 313, #4, p.2431-2432.
Driving while using Marijuana
The higher the blood THC
concentration the higher the variability
in speed and lane position.
In driving simulators higher TCH levels
are correlated with decreased reaction
time
Altered sense of time
Decreased eye-hand coordination
Use of MJ and Alcohol together get
impairment at lower doses
Hartman, R. L., Brown, T. L, et. al. Drug Alcohol Dependence 2015, vol 154, p. 25-37.
Fatal Traffic Crashes and Marijuana
Authors hypothesized that the “High
Holiday” might be associated with an
increase in traffic crashes
Looked at data from the National
Highway Traffic Safety Administration
Accidents in which at least one person
died within 30 days of the “High
Holiday”
25 years of data 1992-2016
Staples, J. A. and Redelmeier, D. A. JAMA Internal Medicine 2018
Fatal Traffic Crashes and Marijuana
Authors hypothesized that the “High
Holiday” might be associated with an
increase in traffic crashes
Looked at data from the National
Highway Traffic Safety Administration
Accidents in which at least one person
died within 30 days of the “High
Holiday”
25 years of data 1992-2016
On 4/20 there were 7.1 drivers in fatal
crashes per hour vs 6.4 drivers in fatal
crashes per hour on control days
RR = 1.12, 95% CI (1.05-1.19), P = 0.001
Risk may be highest for the young
Staples, J. A. and Redelmeier, D. A. JAMA Internal Medicine 2018
Fatal Traffic Crashes and Marijuana
Authors hypothesized that the “High
Holiday” might be associated with an
increase in traffic crashes
Looked at data from the National
Highway Traffic Safety Administration
Accidents in which at least one person
died within 30 days of the “High
Holiday”
25 years of data 1992-2016
On 4/20 there were 7.1 drivers in fatal
crashes per hour vs 6.4 drivers in fatal
crashes per hour on control days
RR = 1.12, 95% CI (1.05-1.19), P = 0.001
Risk may be highest for the young
Staples, J. A. and Redelmeier, D. A. JAMA Internal Medicine 2018
Cognitive Effects: American College
of Obstetrics and Gynecology
When Cannabis is used during
pregnancy the following have been
noted in children:
Cognitive delays/deficits
Impaired executive function
Low birth weight
Intrauterine growth restriction
Stillbirth
Counsel and offer treatment to
patients thinking of becoming
pregnant or who are pregnant
Remission of Cannabis Use Disorder
Of people who try cannabis 9% will develop a problem with cannabis use disorder
Majority of people are able to stop on their own
Females are more likely than males to develop dependence
Tolerance develops in both animals and humans
Treatments
Psychotherapeutic approaches – MI, Family Structural Therapy, CBT-Relapse Prevention, Contingency management
N-Acetylcysteine – 1200mg BID, trial by Gray et. al. (2012) AJP showed 2.4 x more negative utox for MJ
Gabapentin – 1200 BID, reduced use by self report
Nabilone – in clinical trials
Combination therapies possibly promising– in clinical trials
Conclusions
Explore what marijuana use means for
your particular patient
Help patients understand the risks of
synthetic cannabinoids
If you do certify patients for medical
marijuana document:
Advised patient not to drive when using
marijuana
Advised patient not to mix marijuana with
other substances
Advised patient regarding psychiatric risks
Encourage adolescents to avoid
marijuana
Aggressively refer adolescents and
pregnant women for treatment
Cannabis compounds are potentially
promising treatments for myriad
illnesses but further high quality
research is needed
Thank You!!!